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Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25 Page 9 of 14

Drug resistance
HCV is a highly variable virus with a large viral population and numerous quasispecies turnover in an
infected individual. Its life cycle remains confined to the cytoplasm in cell with little possibility of its genome
integration with host genome. Treatment of chronic HCV infection is based on the combination of PegIFN-α
and ribavirin. The use of DAAs against HCV demonstrates that these agents may give rise to drug resistant
viral species. These viral variants have different amino acid composition on target sites and so, are less
susceptible to drug action . In fact, the variants preexist before treatment, possibly arising from error prone
[128]
activities of HCV-RNA dependent RNA polymerase (RdRp) and rarely detected by current techniques.
[129]
Drug exposure inhibits replication of the dominant drug-sensitive viral population to the level of appearance
of resistant variants. In vivo, viral resistance is influenced by three major factors including the genetic
barrier to resistance, in vivo fitness of the viral variant population and drug exposure. Different studies have
indicated that the variants show resistance to NS3/4A protease inhibitors, nucleoside/nucleotide analogues,
non-nucleoside RNA-dependent RNA polymerase inhibitors, NS5A as well as cyclophilin inhibitors . In
[130]
view of these alterations, the drug resistant variants may cause a serious challenge to infection and therefore,
this problem needs a solution by more extensive investigations.

CONCLUSION
This study concludes that the use of PegIFN-α and ribavirin is still a major part of standard of care (SOC)
and the control of HCV infection. The addition of new drugs including DAAs, cyclophilins and miravirsen,
etc. has made a significant improvement in SVR even in those patients where HCV genotypes remain
resistant to PegIFN-α plus ribavirin drug regimen. These drugs target and inhibit viral proteases and cell
receptor proteins as well as enzymes facilitating viral entry into the cell and viral replication and assembly
inside the cell. A check on viral entry as well as their cell to cell transmission or further replication by
the use of these drugs achieves the aim of treatment. In spite of an increase in SVR, the effect of DAAs is
altered by the viral and cellular factors. Basic viral load and viral genotypes were found to show a significant
effect on therapeutic outcome. Similarly, some disease conditions or cellular genomic polymorphism like
IL28B polymorphism also have an impact on drug therapy. The development of drug resistant HCV variants
during viral propagation still remains a serious challenge and needs to be resolved by different combination
or development of new drugs. Studies are in progress looking towards new aspects of drug therapy against
HCV infection.

DECLARATIONS
Acknowledgments
We appreciate the infrastructure provided by All India Institute of Medical Sciences, New Delhi, India, for
the conduct of this study.

Authors’ contributions
All authors have made equal contributions in the performance of study, compilation of data and preparation
of the manuscript.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
The authors declare that there are no conflicts of interest related to this study.